Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/721—Dextrans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/717—Celluloses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/785—Polymers containing nitrogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to pharmaceutical combinations, compositions and methods for treating obesity. More particularly, the invention relates to a combination or composition comprising a lipase inhibitor, preferably a compound of formula I (orlistat),
• a pharmaceutically acceptable bile acid sequestrant and optionally one or more pharmaceutically acceptable excipient(s), e.g. a diluent or carrier.
• Bile acids are synthesized in the liver and enter the bile as glycine and taurine conjugates. They are released in salt form in bile during digestion and act as detergents to solubilize and consequently aid in digestion of dietary fats. Following digestion, bile acid salts are mostly reabsorbed in the ileum, complexed with proteins, and returned to the liver through the hepatic portal vein. The small amount of bile acid salts which are not reabsorbed by active transport are excreted via the distal ileum and large intestine as a portion of fecal material.
• Reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acid circulating in the enterohepatic system thereby potentially reducing emulsification in the upper intestinal tract of dietary fat and reducing intestinal absorption of fat soluble drugs.
• One method of reducing the amount of bile acids that are reabsorbed, is oral administration of compounds that sequester the bile acids within the intestinal tract and cannot themselves be absorbed.
• Orlistat (XENICAL", tetrahydrolipstatin) is a potent inhibitor of gastrointestinal Upases, i.e. Upases which are responsible for breaking down ingested fat (gastric lipase, carboxylester lipase, pancreatic lipase). As a consequence of this, unabsorbed fat is excreted in the faeces. Pancreatic lipase is the key enzyme for the hydrolysis of dietary triglycerides. Triglycerides, which have escaped hydrolysis are not absorbed in the intestine. In pharmacological studies with humans potent inhibition of fat absorption and medically relevant reduction of body weight was demonstrated. However, in a subgroup of the patients unpleasant gastrointestinal side effects such as oily spotting, fatty/ oily stools, fecal urgency, increased defecation and fecal incontinence are observed.
• compositions which are able to minimize or suppress the above mentioned side effects caused by inhibitors of digestive Upases.
• compositions or combinations comprise a lipase inhibitor, preferably orlistat, a pharmaceutically acceptable bile acid sequestrant, optionally in conjunction with a pharmaceutically acceptable excipient, e.g. a diluent or carrier.
• the invention comprises also a method of treatment of obesity and associated comorbidities and other diseases treatable by lipase inhibitors which comprises administration of a therapeutically effective amount of a lipase inhibitor, preferably orlistat, and a therapeutically effective amount of a bile acid sequestrant.
• the present invention relates to a pharmaceutical composition or combination
• a lipase inhibitor preferably a compound of formula I (orlistat) and a pharmaceutically acceptable bile acid sequestrant, optionally in conjunction with a pharmaceutically acceptable excipient, e.g. a diluent or carrier.
• the pharmaceutically acceptable bile acid sequestrant maybe selected from the group consisting of cholestyramine, colestipol, diethylaminoethylcellulose (DEAE-cellulose), and starch derivatives like ⁇ -cyclodextrin and ⁇ -cyclodextrin, more preferably from cholestyramine, colestipol, diethylaminoethylcellulose, ⁇ -cyclodextrin, and ⁇ -cyclodextrin, and even more preferably from cholestyramine and colestipol, and most preferably the bile acid sequestrant is cholestyramine.
• the invention also provides the use of the above combination of compounds in the manufacture of a medicament for the treatment and prevention of obesity. Additionally, it provides the combination for use in the treatment and prevention of obesity.
• pharmaceutically acceptable salts means salts of lipase inhibitors or bile acid sequestrants with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non-toxic to living organisms.
• pharmaceutically acceptable salts mean correspondingly chlorides, bromides, sulphates, phosphates, citrates, formiates, maleates, acetates, succinates, tartrates, methanesulphonates, p-toluenesulphonates and the like.
• lipase inhibitor refers to compounds which are capable of inhibiting the action of Upases, for example gastric and pancreatic Upases.
• Upases for example gastric and pancreatic Upases.
• orlistat and lipstatin as described in U.S. Patent No. 4,598,089 are potent inUibitor of Upases.
• Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin.
• OtUer lipase inhibitors include a class of compound commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al, 1994).
• lipase inhibitor refers also to polymer bound lipase inhibitors for example described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they have been substituted with one or more groups that inhibit Upases.
• lipase inhibitor also comprises pharmaceutically acceptable salts of these compounds.
• lipase inhibitor also refers to 2-oxy-4H-3,l- benzoxazin-4-ones which have been described in International Patent Application WO00/40569 (Alizyme Therapeutics Ltd.), e.g.
• lipase inhibitor refers to orlistat.
• Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Patent No. 4,598,089, issued July 1, 1986, which also discloses processes for making orlistat and U.S. Patent No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123. Additional processes for tUe preparation of orlistat are disclosed in European Patent Applications Publication Nos. 185,359, 189,577, 443,449, and 524,495.
• Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to tUree times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day.
• the subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater.
• the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat.
• treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
• Orlistat can be administered to humans in conventional oral compositions, such as tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions.
• carriers which can be used for tablets, coated tablets, dragees and hard gelatin capsules are lactose, other sugars and sugar alcohols like sorbitol, mannitol, maltodextrin, or other fillers; surfactants like sodium lauryle sulfate, Brij 96, or Tween 80; disintegrants like sodium starcU glycolate, maize starcU or derivatives thereof; polymers like povidone, crospovidone; talc; stearic acid or its salts and the like.
• Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
• tUe pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. They can also contain still other therapeutically valuable substances.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art. Preferably, orlistat is administered according to the formulation shown in the Examples and in U.S. Patent No. 6,004,996, respectively.
• bile acid sequestrant refers to compound classes which are able to bind bile acids or bile acid salts by various principles, e.g. anion exchanging polymers containing amino groups, quaternary ammonium groups, etc. (amine containing polymers).
• the term refers to oligomers or polymers of different architecture (graft-, block-, multiblock-, homo-, copolymers), dendrimers, or hyperbranched structures containing either quaternary ammonium groups, substituted or unsubstituted pyridinium groups, substituted or unsubstituted primary, secondary, or tertiary alkyl- or arylamine groups, or any statistical or non-statistical combination thereof, which are capable of forming complexes with physiologically active bile acids and/ or bile salts through non-covalent Van der Waals, hydrophobic and/or ionic interactions.
• these structures can include, e.g., poly(amino acids) such as poly(lysine), poly(lactic acid-co-lysine) (PLAL), poly(vinyl amine), poly(allyl amine), poly(N-alkylvinyl amine), poly(N,N-dialkyl amine), poly(N-alkylallyl amine), poly(ethylene imine) and other mono- or disubstituted poly(amine)s.
• poly(amino acids) such as poly(lysine), poly(lactic acid-co-lysine) (PLAL), poly(vinyl amine), poly(allyl amine), poly(N-alkylvinyl amine), poly(N,N-dialkyl amine), poly(N-alkylallyl amine), poly(ethylene imine) and other mono- or disubstituted poly(amine)s.
• poly(amino acids) such as poly(lysine), poly(lactic acid-co-lysine) (PLAL
• polymers include poly( vinyl pyridinyl), poly( amide enamines), PAMAM dendrimers, polymers containing azo-groups, poly(dialkyl siloxane)s, poly(phosphazene)s, poly(acrylate)s, poly(methacrylate)s, poly(styrene), poly( amides), poly(ethers), poly( esters).
• Suitable side- chains can include cationic or neutral groups, substituted and unsubstituted aUcyl or aryl groups, saturated or unsaturated aUcyl groups, amino acids or functional groups such as amine or ammonium moieties, for example (Uhrich et. al., Chem. Rev.
• bile acid sequestrants are compounds capable of forming host- guest inclusion complexes, such as ⁇ and ⁇ -cyclodextrines.
• Bile acid sequestrants and methods for their preparation have been described for example in International Patent Applications WO95/34585 (Geltex Pharmaceuticals, Inc.; relating to polyamine salt hydrophobic sequestrants), WO94/27620 (Geltex
• amine containing polymers may comprise the compounds described in International Patent Application WO94/27620.
• the polymers are characterized by a repeat unit having the formula
• each R 4 , R 5 , and R 6 independently, is H, an alkyl group (which ma be straight chain or branched, substituted or unsubstituted, e.g., Ci -C 8 alkyl, such as methyl), or an aryl group (e.g., having one or more rings and which may be substituted or unsubstituted, e.g., phenyl, naphfhyl, imidazolyl, or pyridyl).
• an alkyl group which ma be straight chain or branched, substituted or unsubstituted, e.g., Ci -C 8 alkyl, such as methyl
• an aryl group e.g., having one or more rings and which may be substituted or unsubstituted, e.g., phenyl, naphfhyl, imidazolyl, or pyridyl.
• the polymer is crosslinked by means of a multifunctional crosslinking co-monomer, the co-monomer being present in an amount from about 0.5-25% (more preferably about 2.5- 20% (or about 1-10%)) by weight, based upon total monomer weight.
• the compositions are non-toxic and stable when ingested in therapeutically effective amounts. The preparation of these compounds is described in International Patent Application WO94/27620 (Geltex Pharmaceuticals Inc.).
• bile acid sequestrants also refer to compounds obtainable by molecular imprinting.
• Molecular imprinting is based on template polymerization in which polymers are prepared in the presence of a template molecule to be imprinted. Resulting polymers record the shapes and chemical properties of the templates in their matrixes and exhibit specific binding characteristics to the template molecule.
• the most significant advantage of this technique is to provide a simple procedure for the preparation of synthetic polymers capable of molecular recognition: complementary sites for the target molecules which are expected to be specific binding sites can be constructed with the aid of molecular self- assembling and no complicated synthesis is necessary.
• Molecular imprinted polymers have been described and the effectiveness of molecular imprinted polymers have been demonstrated (Ansell et al. Curr. Opin.
• Imprinted polymers have been used for the chromatographic separation of amino acids, sugars, drugs and nucleotides. Drugs have been measured using imprinted polymers as antibody substitutes in radioligand binding assays (Sheaet al. Trends Polym. Sci. (1994), 2(5), 166- 73; Takeuchi et al. Chromatography (1997), 18(2), 102-103; Nicholls . Molecular Recognition, (1988) 11 (1-6), 79-82).
• the term "bile acid sequestrants” also comprises pharmaceutically acceptable salts of these compounds.
• the invention refers to compositions or combinations wherein the pharmaceutically acceptable bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose and dextran derivatives, starch and starch derivatives and pharmaceutically acceptable salts thereof.
• the pharmaceutically acceptable bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose and dextran derivatives, starch and starch derivatives and pharmaceutically acceptable salts thereof.
• Cholestyramine (Quantalan", Bristol-Myers Squibb) is a known compound and described for example in U.S. Patent No. 4,902,501 and the references cited therein. It is a strong cationic resin containing quaternary ammonium functional groups bonded to a polymeric styrene-divinylbenzene structure:
• Colestipol (Cholestabyl " , Pharmacia & Upjohn) is a known compound and described for example in US Patents Nos. 3,692,895, 3,803,237, and 5,807,582 and the references cited therein. It is a basic anion exchange resin described as a high molecular weight copolymer of diethylenetriamine and l-chloro-2,3-epoxypropane (epichlorohydrin), with approximately one out of 5 amine nitrogens protonated, i.e. it is a copolymer of diethylenetriamine and epichlorohydrin with about 1 out of 5 amine nitrogens protonated:
• Colestipol hydrochloride is commercially available in granule form as Colestid ® Granules. See Physicians Desk Reference (PDR) 42nd Ed., p. 2119 (1988). Colestid® Granules are marketed as a hyperlipidemia agent for oral use. Colestipol binds bile acids in the intestine forming a complex that is excreted in the faeces. This nonsystemic action results in a partial removal of the bile acids from the enterohepatic circulation, preventing their reabsorption.
• Colesevelam and colesevelam hydrochloride are cholesterol-lowering agents (Polym. Prepr. 2000, 41, 735-736).
• Colesevelam is a polyamine-copolymer of the three amines mentioned below, which are cross-linked with epichlorhydrine.
• Sevelamer and its hydrochloride (Renagel” , GelTex) is a polymeric phosphate binder intended for oral administration.
• Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which forty percent of the amines are protonated:
• Colestimide (CUolebine ® ; MitsubisUi-Tokoyo PUarmaceuticals) is a 2- methylimidazole polymer with l-chloro-2,3-epoxypropane:
• DEAE-cellulose, guanidinoethylcellulose, and DEAE-Sephadex reduce hypercholesterolemia when added to the diet of cholesterol-fed cockerels.
• DEAE-Sephadex reduced serum sterols in normocholesterolemic cockerels and dogs, lowered serum phospholipids and triglycerides in cUolesterol-fed hypercholesterolemic cockerels and in normocholesterolemic dogs, and increased fecal excretion of bile acids in hypercholesterolemic cockerels.
• DEAE-celluloses are compounds wUerein diethylaminoetUyl- groups are covalently bound to the cellulose hydroxylic groups.
• DEAE-celluloses are known substances and commercially available (e.g. Sigma- Aldrich).
• Guanidinoethylcelluloses are compounds wherein guanidinoethyl-groups are covalently bound to the cellulose hydroxylic groups. Guanidinoethylcelluloses are known substances and commercially availalbe.
• DEAE-Sephadex is a cross-linked dextran derivative wherein diethylaminoethyl-groups are covalently bound to dextran.
• DEAE-Sephadex compositions are commercially availalbe (e.g. Pharmacia Fince Chemicals).
• DEAE-cellulose, guanidinoethylcellulose and DEAE-Sephadex are especially useful as bile sequestrant agent, preferably DEAE-cellulose.
• starch and derivatives thereof comprise compounds which are able to form inclusion complexes with free and conjugated bile salts and bile acids.
• examples are ⁇ -, and ⁇ -cyclodextrin, which contain, respectively, seven, and eight anhydroglucose (C 6 H 10 O 5 ) units.
• These molecules are doughnut-shaped rings having a hollow cavity of a specific volume. The polar hydroxyl groups are oriented to the outside of the rings, giving the outer surface a hydrophilic nature. In contrast, the internal cavity has a hydrophobic (lipophilic) nature.
• cyclodextrins as the "host” molecules, are able to hold "guest” molecules of suitable size (generally of a molecular weight between 80 and 250), shape, and hydrophobicity within their cavity.
• guest molecules generally of a molecular weight between 80 and 250
• ⁇ -, and ⁇ -cyclodextrin are commercially available compounds (e.g. Sigma- Aldrich).
• Other examples of starch and derivatives thereof are retrograded and/or degraded starch e.g. maltodextrin, hydrophobic starch, amylose, and starch derivatives, e.g.
• starch- diethylaminoethylether, starch-2-hydroxyethylether and the like ("Lexikon der Hilfsstoffe fur PUarmazie, Kosmetik und angrenzende füre", H. P. Fiedler, Editio Cantor Aulendorf, Bd. 2., 3. Aufiage, 1989, pp. 1147-1154).
• starch derivatives are selected from the group consisting of consisting of ⁇ - or ⁇ - cyclodextrin, retrograded and/or degraded starch, e.g.
• maltodextrin hydrophobic starch, amylose, starch- diethylaminoethylether and starch-2-hydroxyethylether, preferably from ⁇ - or ⁇ - cyclodextrin (Wacker Chemie; Gattfosee).
• the bile acid sequestrant is a cellulose or dextran derivative, e.g. DEAE-cellulose, guanidinoethylcellulose, and DEAE-Sephadex, preferably DEAE-cellulose.
• the starch or starch derivative is selected from the group consisting of ⁇ - or ⁇ -cyclodextrin, retrograded and/or degraded starch, hydrophobic starch, amylose, starch-diethylaminoethylether and starch- 2-hydroxyethylefher, preferably ⁇ - or ⁇ -cyclodextrin.
• the bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose, DEAE-cellulose, guanidinoethylcellulose, and DEAE-Sephadex, starch, ⁇ - or ⁇ - cyclodextrin, preferably cholestyramine, colestipol, colesevelam, colestimide, sevelamer, DEAE-cellulose, and ⁇ - or ⁇ - cyclodextrin, more preferably cholestyramine, colestipol, sevelamer, DEAE-cellulose, and ⁇ - or ⁇ - cyclodextrin, most preferably cholestyramine, colestipol, and sevelamer.
• the bile acid sequestrant is cholestyramine. In a further preferred embodiment, the bile acid sequestrant is colestipol. In a additional embodiment the bile acid sequestrant is sevelamer.
• compositions incorporating both a compound of a lipase inUibitor and a bile acid sequestrant are important embodiments of the present invention.
• Such pharmaceutical compositions comprise a therapeutically effective amount of each of the compounds.
• Each dosage unit can obtain the daily doses of both compounds or may contain a fraction of the daily dose, such as one-third of the doses.
• each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compound. In such case the patient would daily take one of the combination dosage units, and one or more units containing only the other compound.
• compositions comprising a) about 5 to about 1000 mg lipase inhibitor and b) about 0.1 to about 20 g bile acid sequestrant.
• the compositions may comprise a pharmaceutically acceptable excipient, e.g. a diluent or carrier.
• the pharmaceutically acceptable excipient may be selected from the group consisting of fillers, e.g. sugars and/or sugar alcohols, e.g. lactose, sorbitol, mannitol, maltodextrin, etc.; surfactants, e.g. sodium lauryle sulfate, Brij 96 or Tween 80; disintegrants, e.g.
• sodium starch glycolate, maize starch or derivatives thereof e.g. povidone, crosspovidone, polyvinylalcohols, hydroxypropylmethylcellulose; lubricants, e.g. stearic acid or its salts; flowability enhancers, e.g. silicium dioxide; sweeteners, e.g. aspartame; and/or colorants, e.g. ⁇ -carotene.
• binder e.g. povidone, crosspovidone, polyvinylalcohols, hydroxypropylmethylcellulose
• lubricants e.g. stearic acid or its salts
• flowability enhancers e.g. silicium dioxide
• sweeteners e.g. aspartame
• colorants e.g. ⁇ -carotene.
• a preferred composition may comprise a) about 5 to about 1000 mg lipase inUibitor; b) about 0.1 to about 20 g bile acid sequestrant; and optionally pharmaceutically acceptable excipients selected from tUe group of about 0.1 to about 10 g fillers, about 0.05 to about 3.0 g surfactant, about 0.05 to about 2.0 g disintegrant, about 0.02 to about 2.0 g binder, about 0.001 to about 1.0 g lubricant, about 0.1 to about 5.0 g flowability enbancer, about 0.01 to about 4.0 g sweetener, and about 0.001 to about 0.5 g colorant.
• the preferred lipase inhibitor is orlistat.
• tUe invention refers to pharmaceutical compositions comprising orlistat, a pharmaceutically acceptable bile acid sequestrant in conjunction witU a pharmaceutically acceptable excipient, e.g. a diluent or carrier, preferably to compositions wherein the pharmaceutically acceptable bile acid sequestrant is selected from as defined above.
• compositions containing both a lipase inhibitor, e.g. orlistat and a bile acid sequestrant as described above may comprise 5 to 1000 mg lipase inhibitor, preferably about 10 to about 500 mg lipase inhibitor, more preferably about 20 to about 100 mg lipase inhibitor, e.g. orlistat.
• TUe preferred amounts for orlistat are about 10 to about 360 mg, preferably about 30 to about 120 mg and most preferably about 40 to about 80 mg.
• TUe pharmaceutical compositions may contain about 0.1 to about 20 g bile acid sequestrant, preferably about 0.5 to about 10 g, and most preferably about 1 to about 5 g.
• TUe invention also refers to a process for preparing a composition as described above, comprising mixing a lipase inUibitor or a pbarmaceutically acceptable salt tUereof witU a bile acid sequestrant or a pharmaceutically acceptable salt tUereof and one or more pharmaceutically acceptable excipient, e.g. a diluent and/or carrier.
• a lipase inUibitor or a pbarmaceutically acceptable salt tUereof witU a bile acid sequestrant or a pharmaceutically acceptable salt tUereof
• one or more pharmaceutically acceptable excipient e.g. a diluent and/or carrier.
• Oral dosage forms are tUe preferred compositions for use in tUe present invention and tUese are tUe known pUarmaceutical forms for such administration, for example tablets, capsules, bars, sachets, granules, syrups and aqueous or oily suspensions.
• the pharmaceutically acceptable excipients are known in the pharmacist's art.
• Tablets may be formed from a mixture of the active compounds with fillers, for example calcium phosphate; disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate; binders, for example microcrystaUine cellulose or polyvinylpyrrolidone and otUer optional ingredients known in tUe art to permit tabletting the mixture by known methods.
• capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
• the tablets and capsules may conveniently each contain the amounts of lipase inhibitor and bile acid sequestrant as described above.
• the active compounds may be formulated into granules with or without additional excipients.
• the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (e.g. water) before ingestion.
• TUe granules may contain disintegrants, e.g. an effervescent pair formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in tUe liquid medium.
• tUe active compounds may, if desired, be associated witU otUer compatible pharmacologically active ingredients.
• vitamin supplements maybe administered with the compounds of the present invention.
• Both compounds, the lipase inUibitor and tUe bile acid sequestrant may be administered simultaneously, separately or sequentially.
• tUe compounds or compositions are administered during a meal or 1 - 2 Uours before or after a meal.
• TUe amount of bile acid sequestrant to be administered will depend on a number of factors including tUe age of tUe patient, tUe severity of tUe condition and tUe past medical Uistory of tUe patient and lies within tUe discretion of the administering physician.
• ⁇ - and ⁇ - cyclodextrin starch derivatives
• cholestyramine colestipol
• colestipol amine containing polymer
• diethylaminoethylcellulose cellulose or dextran derivative
• the invention also provides the use of the above combination of compounds in the manufacture of a medicament for the treatment and prevention of obesity. Additionally, it provides the combination and above compositions for use in the treatment and prevention of obesity.
• the invention also refers to a kit for treatment of obesity, said kit comprising a first component which is a lipase inUibitor and b) a second component wUicU is a bile acid sequestrant e.g. in an oral unit dosage forms, preferably comprising a) from 1 to 100 doses units of orlistat and b) from 1 to 100 doses units of a bile acid sequestrant.
• a kit for treatment of obesity comprising a first component which is a lipase inUibitor and b) a second component wUicU is a bile acid sequestrant e.g. in an oral unit dosage forms, preferably comprising a) from 1 to 100 doses units of orlistat and b) from 1 to 100 doses units of a bile acid sequestrant.
• FurtUer, tUe present invention refers to tUe use of a composition as described above in tUe manufacture of medicaments useful for tUe treatment and prevention of obesity, e.g. tUe use of a lipase inUibitor in tUe manufacture of a medicament for tUe treatment and prevention of obesity in a patient wUo is also receiving treatment witU a bile acid sequestrant or a pharmaceutically acceptable salt tUereof.
• BotU compounds, tUe lipase inUibitor and tUe bile acid sequestrant may be administered simultaneously, separately or sequentially.
• tUe present invention also relates to a lipase inUibitor and a bile acid sequestrant as defined above for tUe simultaneous, separate or sequential use for the treatment and prevention of obesity and to a combined preparation for simultaneous, separate or sequential use for the treatment and prevention of obesity.
• the invention also refers to the use of a bile acid sequestrant as defined above in the manufacture of medicaments useful for the treatment and prevention of gastrointestinal side effects selected from the group of oily spotting, fatty/oily stools, fecal urgency, increased defecation and fecal incontinence. Further, the invention also refers to a method of treatment or prevention of gastrointestinal side effects selected from the group of oily spotting, fatty/oily stools, fecal urgency, increased defecation and fecal incontinence in a human in need of such treatment which comprises administration to the human of a therapeutically effective amount of of a bile salt sequestrant as defined above.
• TUe model is based on tUe idea tUat GI side effects foUowing orlistat ingestion are precipitated by tUe formation of free oil. Free oil is oil, wUicU will coalesce in tUe dietary fat emulsion passing down tUe GI tract and separate from tUe stool matrix. In this model the amount of oil which is separated from the stool matrix is determined after the production of stools.
• Blend orlistat, microcrystaUine cellulose, and sodium starcU glycolate in a suitable mixer Blend orlistat, microcrystaUine cellulose, and sodium starcU glycolate in a suitable mixer.
• Blend orlistat, lactose, microcrystaUine cellulose and sodium starch glycolate in a suitable mixer Blend orlistat, lactose, microcrystaUine cellulose and sodium starch glycolate in a suitable mixer.
• Granulate with a solution of polyvinylpyroUidone and sodium lauryl sulfate in purified water.
• Granulate witU a solution/ colloidal suspension of aspartame and beta-carotene in purified water.
• Granulate with a solution/colloidal suspension of sodium lauryl sulfate, aspartame in purified water.

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